Circulatory diseases caused by hypertension, hyperlipemia or hyperglycemia and so forth (such as heart disease, cerebrovascular disease or kidney disease) are becoming a serious problem in advanced countries. An antihypertensive medicine, an antihyperlipemic medicine and an antidiabetic medicine are used for the treatment of hypertension, hyperlipemia and hyperglycemia, respectively. In the clinical setting, α- and β-blockers, diuretics, calcium antagonists, ACE inhibitors, A-II antagonists and so forth are used as an antihypertensive medicine; HMG-CoA reductase inhibitors, anion exchange resins, nicotinic acid derivatives, probucol, fibrates and so forth are used as an antihyperlipidemic medicine; and insulin, sulfonylureas, metformin, glitazones and so forth are used as an antidiabetic medicine. These medicines contribute to regulation of blood pressure and lipid or glucose levels in the blood. However, since the use of these medicines has not resulted in a remarkable improvement of the mortality rates due to heart disease, cerebrovascular disease and kidney disease, there is a need for the development of a superior therapeutic medicine for these diseases.
A direct risk factor of circulatory disease is arteriosclerosis accompanying hypertrophy of artery walls, and the cause of this hypertrophy is the formation of plaque resulting from accumulation of oxidized low-density lipoprotein cholesterol (LDL-C) on artery walls (Ross, R., Annu. Rev. Physiol., 57, pp. 791-804, 1995; Steinberg, D., J. Biol. Chem., 272, pp. 20963-20966, 1997). This plaque inhibits the flow of blood and promotes the formation of thrombi.
The nuclear receptor, LXR, has recently been determined to play an important role in the regulation of lipid metabolism (Janowski, B. A., Willy, P. J., Falck, J. R., Mangelsdorf, D. J., Nature, 383, pp. 728-731, 1996). LXR has two types of isoforms consisting of LXRα and LXRβ. LXRα is highly distributed in the liver of mammals and only distributed in small amounts in the kidney, small intestine, spleen and adrenals, while LXRβ is distributed in organs and tissues throughout the body. LXR is subject to regulation of transcription by oxidized sterol present in macrophages of vascular walls, induces an expression of ABCA1 (ATP binding cassette transporter-1) and ApoE (apolipoprotein E), and promotes extraction of cholesterol from vascular walls and reverse cholesterol transport to the liver (Lu, T. T., Repa, J. J., Mangelsdorf, D. J., J. Biol. Chem., 276, pp. 37735-37738, 2001). In addition, LXR induces expression of ABCA1 in the small intestine, and inhibits absorption of dietary cholesterol from the digestive tract (Repa, J. J., Turley, S. D., Lobaccaro, J. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dietschy, J., Mangelsdorf, D. J., Science, 289, pp. 1524-1529, 2002). In consideration of the importance of LXR in cholesterol metabolism, medicines which regulate LXR can be expected to be useful in the treatment or prevention of arteriosclerosis, atherosclerosis, arteriosclerosis caused by diabetes, hyperlipemia, lipid-associated diseases, arteriosclerotic heart disease, cardiovascular disease or coronary artery disease.
Atherosclerosis is also considered to be a chronic inflammatory disease (Ross, R., N. Engl. J. Med., 314, pp. 488-500, 1986). LXR has recently been reported to play an important role in the control of immune functions by regulating the expression of inflammatory mediators such as nitric oxide synthase, cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) (Mangelsdorf, D. J., Tontonoz, P., et al., Nat. Med., 9, pp. 213-219, 2003). Thus, in addition to improving lipid metabolism, LXR modulators are expected to inhibit the onset and progression of arteriosclerosis by improving lipid metabolism as well as anti-inflammatory action. Moreover, naturally-occurring and synthetic LXR activators have been shown to reduce chemically-induced dermatitis in animal models (Fowler, A. J., et al., J. Invest. Dermatol., 120, pp. 246-255, 2003). In this manner, LXR modulators are expected to be useful for the treatment of various inflammatory diseases.
Although benzene compounds having two or more substituents showing an LXR regulatory effect (namely, having an effect on the expression of ABCA1) are known, their structures differ to that of the compound of the present invention (see Patent documents 1 and 2).
[Patent Document 1]
International Patent Publication No. 2004/026816 pamphlet
[Patent Document 2]
International Patent Publication No. 2002/024632 pamphlet